<p>This study involved the chemical modification of xanthan gum to carboxymethyl xanthan (CMX) gum, which was then oxidized with periodate for different periods of time (2–10&#xa0;min) to achieve different degrees of oxidation (22–31%). Fourier transform infrared (FTIR) spectroscopy were used to characterize the modified polymers. The degree of carboxymethylation were also determined to confirm the modification. Oxcarbazepine-loaded hydrogel microspheres were prepared using oxidized CMX through Al³⁺-ion-induced gelation, L-lysine-mediated Schiff base conjugation, and Steglich esterification. A three-factor, three-level Box-Behnken design was used to optimize the formulation factors. The mean diameter of the optimized L-lysine crosslinked microspheres was 910 ± 35&#xa0;μm, and their drug entrapment efficiency was 83.96 ± 2.64%. Field emission scanning electron microscopy (FESEM) images showed that the microspheres became spherical after drug loading. FTIR spectroscopy study revealed no chemical interactions between the drug and the polymer. Nevertheless, thermal and x-ray examinations showed that while the remaining drug crystals were uniformly distributed throughout the matrix, some of them changed into Form II. Under simulated gastrointestinal pH, the microspheres showed no signs of matrix disruption and only released 64% of the drug in 12&#xa0;h. The drug release followed a non-Fickian process that combines polymer relaxation and diffusion. Overall, the L-lysine treatment seemed to be a successful green crosslinker for creating stable, pH-sensitive CMX hydrogel for oral regulated delivery of oxcarbazepine. The in vitro controlled drug release behaviour could be beneficial in reducing the peak-to-trough variations in serum drug concentration, which in turn diminish the risk of associated side effects and seizures.</p>